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Mechanisms of Oncolysis by Paramyxovirus Sendai.

ABSTRACT: Some viral strains of the Paramyxoviridae family may be used as anti-tumor agents. Oncolytic paramyxoviruses include attenuated strains of the measles virus, Newcastle disease virus, and Sendai virus. These viral strains, and the Sendai virus in particular, can preferentially induce the death of malignant, rather than normal, cells. The death of cancer cells results from both direct killing by the virus and through virus-induced activation of anticancer immunity. Sialic-acid-containing glycoproteins that are overexpressed in cancer cells serve as receptors for some oncolytic paramyxoviruses and ensure preferential interaction of paramyxoviruses with malignant cells. Frequent genetic defects in interferon and apoptotic response systems that are common to cancer cells ensure better susceptibility of malignant cells to viruses. The Sendai virus as a Paramyxovirus is capable of inducing the formation of syncytia, multinuclear cell structures which promote viral infection spread within a tumor without virus exposure to host neutralizing antibodies. As a result, the Sendai virus can cause mass killing of malignant cells and tumor destruction. Oncolytic paramyxoviruses can also promote the immune-mediated elimination of malignant cells. In particular, they are powerful inducers of interferon and other cytokynes promoting antitumor activity of various cell components of the immune response, such as dendritic and natural killer cells, as well as cytotoxic T lymphocytes. Taken together these mechanisms explain the impressive oncolytic activity of paramyxoviruses that hold promise as future, efficient anticancer therapeutics.

SUBMITTER: Matveeva OV

PROVIDER: S-EPMC4463408 | biostudies-literature | 2015 Apr-Jun

REPOSITORIES: biostudies-literature

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Mechanisms of Oncolysis by Paramyxovirus Sendai.

Matveeva O V OV Kochneva G V GV Netesov S V SV Onikienko S B SB Chumakov P M PM

Acta naturae 20150401 2

Some viral strains of the Paramyxoviridae family may be used as anti-tumor agents. Oncolytic paramyxoviruses include attenuated strains of the measles virus, Newcastle disease virus, and Sendai virus. These viral strains, and the Sendai virus in particular, can preferentially induce the death of malignant, rather than normal, cells. The death of cancer cells results from both direct killing by the virus and through virus-induced activation of anticancer immunity. Sialic-acid-containing glycoprot ...[more]

PMID: 26085940

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Project description:One of the first defenses against infecting pathogens is the innate immune system activated by cellular recognition of pathogen-associated molecular patterns (PAMPs). Although virus-derived RNA species, especially copyback (cb)-type defective interfering (DI) genomes, have been shown to serve as real PAMPs, which strongly induce interferon-beta (IFN-?) during mononegavirus infection, the mechanisms underlying DI generation remain unclear. Here, for the first time, we identified a single amino acid substitution causing production of cbDI genomes by successful isolation of two distinct types of viral clones with cbDI-producing and cbDI-nonproducing phenotypes from the stock Sendai virus (SeV) strain Cantell, which has been widely used in a number of studies on antiviral innate immunity as a representative IFN-?-inducing virus. IFN-? induction was totally dependent on the presence of a significant amount of cbDI genome-containing viral particles (DI particles) in the viral stock, but not on deficiency of the IFN-antagonistic viral accessory proteins C and V. Comparison of the isolates indicated that a single amino acid substitution found within the N protein of the cbDI-producing clone was enough to cause the emergence of DI genomes. The mutated N protein of the cbDI-producing clone resulted in a lower density of nucleocapsids than that of the DI-nonproducing clone, probably causing both production of the DI genomes and their formation of a stem-loop structure, which serves as an ideal ligand for RIG-I. These results suggested that the integrity of mononegaviral nucleocapsids might be a critical factor in avoiding the undesirable recognition of infection by host cells.IMPORTANCE The type I interferon (IFN) system is a pivotal defense against infecting RNA viruses that is activated by sensing viral RNA species. RIG-I is a major sensor for infection with most mononegaviruses, and copyback (cb)-type defective interfering (DI) genomes have been shown to serve as strong RIG-I ligands in real infections. However, the mechanism underlying production of cbDI genomes remains unclear, although DI genomes emerge as the result of an error during viral replication with high doses of viruses. Sendai virus has been extensively studied and is unique in that its interaction with innate immunity reveals opposing characteristics, such as high-level IFN-? induction and strong inhibition of type I IFN pathways. Our findings provide novel insights into the mechanism of production of mononegaviral cbDI genomes, as well as virus-host interactions during innate immunity.

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Mechanisms of Oncolysis by Paramyxovirus Sendai.

Publications

Mechanisms of Oncolysis by Paramyxovirus Sendai.

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